Abstract
Hexavalent Chromium [Cr(VI)] compounds are human lung carcinogens and environmental/occupational hazards. The molecular mechanisms of Cr(VI) carcinogenesis appear to be complex and are poorly defined. In this study, we investigated the potential role of Gene 33 (ERRFI1, Mig6), a multifunctional adaptor protein, in Cr(VI)-mediated lung carcinogenesis. We show that the level of Gene 33 protein is suppressed by both acute and chronic Cr(VI) treatments in a dose- and time-dependent fashion in BEAS-2B lung epithelial cells. The inhibition also occurs in A549 lung bronchial carcinoma cells. Cr(VI) suppresses Gene 33 expression mainly through post-transcriptional mechanisms, although the mRNA level of gene 33 also tends to be lower upon Cr(VI) treatments. Cr(VI)-induced DNA damage appears primarily in the S phases of the cell cycle despite the high basal DNA damage signals at the G2M phase. Knockdown of Gene 33 with siRNA significantly elevates Cr(VI)-induced DNA damage in both BEAS-2B and A549 cells. Depletion of Gene 33 also promotes Cr(VI)-induced micronucleus (MN) formation and cell transformation in BEAS-2B cells. Our results reveal a novel function of Gene 33 in Cr(VI)-induced DNA damage and lung epithelial cell transformation. We propose that in addition to its role in the canonical EGFR signaling pathway and other signaling pathways, Gene 33 may also inhibit Cr(VI)-induced lung carcinogenesis by reducing DNA damage triggered by Cr(VI).
Highlights
Cr(VI) compounds are well documented human lung carcinogens [1,2,3]
The activation of γH2AX indicates that Cr(VI) induces DNA damage in the form of DNA double strand breaks (DSBs), confirming the previously published observations [4, 6, 10, 32]
We find that knockdown of Gene 33 in BEAS2B cells elevated the level of Cr(VI)-induced DNA damage, as indicated by increased γH2AX signals in cells transfected with an siRNA oligo for Gene 33 compared to those transfected with a scrambled oligo (Figure 4A, 4B, 4C, 4D)
Summary
Cr(VI) compounds are well documented human lung carcinogens [1,2,3]. Occupational exposure, mainly through inhalation, during industrial processes such as chrome plating, stainless steel production, and chrome pigment manufacturing are the main sources of human contact with Cr(VI) [1,2,3]. Despite the ability of forming potentially mutagenic Cr(III)-DNA ternary adducts during its intracellular reduction process [9], Cr(VI) appears to be a weak mutagen [5]. Epigenetic effects of Cr(VI) which lead to altered histone methylation, histone acetylation, and DNA methylation have been reported and believed to play significant roles in lung carcinogenesis [11, 12]. Despite these previous efforts, the specific mechanisms, the specific intracellular molecular mediators of Cr(VI) carcinogenesis, remain poorly defined
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